The major goal of this overall Program Project is to dissect the role of the steroid receptor coactivator (SRC) family in mediating the tissue- selective biological functions of different steroid hormones and their cognate nuclear receptors. (NRs). Our working hypothesis in this Project is that the specificity of coactivator requirement for NRs in target tissues is a function of (i) the intracellular concentrations of coactivators and liganded NRs and (ii) the inherent affinities between specific liganded NR-coactivator pairs. These tissues will be integrated in three Specific Aims. In Specific Aims 1 and 2, we will set out to determine, using multiple tissues and under conditions of ligand induction or withdrawal and in models of the disease states in which NR signaling pathways are implicated, such as type II diabetes, such as type II diabetes, obesity, hyperlipidemia. In Specific Aim 3, we will generate data on the patterns of coactivator selectivity by different NRs by sensitive measurement of the inherent affinities of individual receptor-coactivator pairs using purified receptors. The results we envisage are essential for our understanding of the tissue-specific biology of members of the SRC family. In addition, these studies will pave the way for a greater understanding of the mode of action of selective receptor modulators (SRMs), and will provide prospects for their therapeutic application in the myriad endocrine and metabolic disorders in which NRs and, by association SRCs, are implicated.